ORIGINS OF ANTIBIOTICS
Accidents in science occasionally lead to great discoveries. We owe the identification
of penicillin to one such serendipitous mishap. Sir Alexander Fleming discovered
the first therapeutic antibiotic in 1929 when a green mold contaminated one of
his bacterial culture dishes. Fleming observed that where the mold had invaded,
the bacterial colonies (Staphylococcus aureus) had disappeared. He realized
that not only did this mold—which was of Penicillium notation—have
antibacterial properties in vitro, but that there was also potential for
using the molds secretions in therapies.
How did the mold get into the dish in the first place? As it turns out, Flemings
lab was upstairs from the lab of a mycologist, and the mold from the mycologists
lab contaminated Fleming's cultures. Although scientists try hard not to contaminate
each others work, their fortunate failure to do so in this instance led
to a discovery that saved millions of lives.
Actually, Fleming was not the first person to recognize the antibacterial properties
of mold. As far back as 2,500 years ago, the Chinese were using treatments made
of moldy soybean curd to treat infections. The ancient Egyptians rubbed moldy
bread on wounds to cure them, and moldy cheese was used for the same purpose
in parts of Europe.
These days, youre not going to scrape the mold off cheese to procure
its antibiotic effects. Myriad antibiotics are available to treat various illnesses,
curing bacterial infections ranging from strep throat to urinary tract infections.
The structure of the cell wall divides bacteria into two groups, the Gram positive
and the Gram negative. Gram-positive bacteria have a thick layer of peptidoglycan,
a sugar and peptide coating that gives a cell its shape and helps it stay intact.
The original antibiotic, penicillin, and its cousins are used to treat infections
caused by bacteria that are Gram positive.
Gram-positive bacteria stain blue-violet in a Gram-staining procedure. Streptococcal
and staphylococcal strains are Gram positive, and these bacteria are responsible
for illnesses such as strep throat, blood poisoning, pneumonia, and toxic shock
syndrome. Other classes of antibiotics, including streptomycins and tetracycline,
effectively destroy both Gram-negative and Gram-positive bacteria, making them
able to fight pathogens such as Shigella or Salmonella.
BACTERIAL RESISTANCE AND HEALTH
Many bacterial strains now resist the effects of antibiotics that once could
destroy them. Every population of bacteria may have some individuals that are
resistant. The proliferation of antibiotics and careless use of the drugs have
given some resistant bacteria the upper hand in the fight against disease.
A patient who is prescribed a 10-day course of antibiotics, but who quits taking
them after a couple of days because the symptoms have subsided, leaves behind
bacteria that resisted the antibiotic effect. Growth of these bacteria may have
slowed in the presence of the antibiotic, but the bacteria are not completely
wiped out. Some resistant bacteria may survive an even longer course of antibiotics
if the dosage of the drug is not high enough. Typically, after a complete, full-strength
antibiotic course, so few resistant bacteria remain that the bodys own immune
system can handle them; however, a short course may leave behind so many resistant
bacteria that they proliferate. These resistant bacteria also have a better chance
to flourish because the other, weaker, bacteria have died. Its the scenario
for a medical crisis.
HISTORY OF DEVELOPMENT OF RESISTANCE
Resistant bacteria have always been around and existed long before humans began using antibiotics therapeutically. What is new in the world of resistance is how quickly new resistant strains arise. The widespread use and misuse of antibiotics contribute to the problem. For the first time in decades, people in the United States are dying of bacterial infections that cannot be treated.
- Right after we began using penicillin, some Staphylococcus strains
were identified as resistant to it.
- Today, 80 percent of Staphylococcus strains do not respond to penicillin.
- In the 1940s and early 1950s, streptomycin, chloramphenicol, and tetracycline were discovered.
- By 1953, a strain of Shigella was found that resisted these antibiotics
- By the 1970s, resistant strains of gonorrhea arose.
- The 1990s saw the development of true superbugs, bacteria that resist all known antibiotics.
- One antibiotic of last resort is Vancomycin, a powerful antibiotic that attacks bacteria on many fronts.
- Now there are Enterococci strains that resist Vancomycin.
- Multi-drug resistant tuberculosis strains have arisen.
- By the 1940s and 1950s, a single antibiotic, such as Streptomycin, no
longer cured tuberculosis, as it had in the past.
- Tuberculosis is the leading cause of death by infectious disease in the world.
WHERE ANTIBIOTICS COME FROM
Below are listed some common antibiotics and their natural sources.
|SOURCES OF ANTIBIOTICS
||Dirt-dwelling organisms that form endospores and create
antibiotics, possibly to deter bacterial competition. These organisms are unaffected
by their own antibiotics, but can be susceptible to other antibiotics. Produce
polypeptide antibiotics (e.g., polymyxin and bacitracin).
|Linezolid (Zyvox)–Treat Gram-positive infections.
Bind rRNA to prevent protein synthesis.
MECHANISMS OF ANTIBIOTIC ACTION
The many modes of antibiotic action are shown schematically in the diagram
Some specific examples
- Penicillin is a -lactam antibiotic.
- These antibiotics contain a -lactam ringthree
carbons and one nitrogen.
- Transpeptidase crosslinks the peptidoglycan net in the cell wall of Gram-positive
- The -lactam ring mimics a component of the cell
wall to which transpeptidase binds.
- Penicillin competitively inhibits the binding of transpeptidase.
- The affected bacterium will eventually lyse (rupture) because the unsupported
cell wall cannot withstand its growth.
Disrupters of nucleic acid synthesis
- RNA polymerase synthesizes RNA according to a DNA template.
- The antibiotic rifampin interferes with prokaryotic RNA polymerase and thus, interferes with transcription.
- Fluoroquinolones inhibit DNA gyrase, a bacterial enzyme that unwinds DNA
in preparation for replication and transcription.
- Both of these disruptions prevent bacteria from dividing to make more bacteria.
Disrupters of protein synthesis
- Aminoglycosides inhibit nucleic acid or protein synthesis in bacteria.
- They are L-shaped molecules that fit into L-shaped pockets of bacterial ribosomal
- When they insert themselves into rRNA, they disrupt ribosomal structure.
- Aminoglycosides dont have this effect on human cells because the L-shaped
pocket is specific to bacteria.
Inhibitors of metabolism
- Inhibit synthesis of purine and thymidylate precursors folic acid or tetrahydrofolate.
- Sulfonomides inhibit bacteria-specific reaction.
OF ACTION OF SELECTED ANTIBIOTICS
|Inhibitors of cell
||Inhibits transpeptidation enzymes. Activates lytic
enzymes of cell wall.
||Inhibits transpeptidase enzymes. Activates lytic enzymes
of cell wall. The affected bacterium will eventually lyse because the unsupported
cell wall cannot withstand its growth.
||Inhibits transpeptidation in cross-linking peptidoglycans.
Interferes with bacterial cells at many levels, disrupting cell wall synthesis,
interfering with RNA, and damaging the plasma membrane.
|Inhibitors of nucleic
||Inhibits DNA gyrase; interferes with DNA replication.
||Blocks RNA synthesis by binding to and inhibiting
|Inhibitors of protein
||Blocks formation of new peptide bonds during protein
synthesis by binding to the 50S subunit of the ribosome.
||Binds the 50S subunit and blocks translocation of
the new protein on the ribosome, thus effectively halting synthesis.
||Binds rRNA to prevent translation initiation and thus
||Binds the 30S ribosomal subunit of the tuberculosis
bacterium and prevents the ribosome from forming the complex necessary to initiate
protein translation. Streptomycin is the first line of chemical defense against
||Binds to the 30S subunit and blocks the addition of
amino acids, producing incomplete and probably nonfunctional proteins.
||Interferes with synthesis of folic acid,
which is required for the synthesis of purines and thymidine and for the synthesis
of the amino acids methionine and gycine.
||Competitively inhibits dihydropteroate
synthase, an enzyme that converts p-aminobenzoic acid (PABA) into folic
acid. These drugs can also be incorporated into a compound that resembles dihydrofolate
and that in turn can inhibit another enzyme in the pathway, dihydrofate reductase.
||Inhibits dihydrofolate reductase, blocking
MECHANISMS OF RESISTANCE
Bacteria either have preexisting resistance to drugs, or they develop resistance. Human activity has contributed greatly to the increase in resistant strains of bacteria. Often, when bacteria acquire resistance to a certain drug from a particular class (e.g., the penicillins), the bacteria also acquire resistance to all other drugs in that class.
Some of the many mechanisms of resistance are indicated schematically in the following diagram:
The principles of Darwinian evolution act on bacteria with inherent resistance:
those bacteria that resist an antibiotic's effects are better suited to survive
in an environment that contains the antibiotic. In the case of inherent resistance
and vertical evolution, the genes that confer resistance are found on bacterial
chromosomes and are transferred to the bacterial progeny every time the cell
- Bacteria may begin life resistant to a particular antibiotic.
- Example: Gram-negative bacteria are naturally resistant to penicillins.
- Bacteria may be resistant because either
- they have no mechanism to transport the drug into the cell.
- they do not contain or rely on the antibiotics target process
- Specific examples of bacterial strains with known natural resistance:
- tetracycline-resistant Proteus mirabilis.
- ampicillin-resistant Klebsiella pneumoniae.
Bacteria that dont begin life resistant to a certain antibiotic can acquire
that resistance. In the case of vertical evolution and inherent resistance, mutations
occur on chromosomes and are then selected for an environment where resistance
increases fitness. In the case of horizontal evolution, genes pass from a resistant
strain to a nonresistant strain, conferring resistance on the latter. The introduction
of an antibiotic alters the environment and acts as a selective pressure.
Transmission of resistance genes via plasmid exchange.
- Bacteria have circles of DNA called plasmids that they can pass to other bacteria during conjugation.
- Plasmids, the key players in conjugation, are even referred to as resistance transfer factors.
- This type of acquisition allows resistance to spread among a population of bacterial cells much faster than simple mutation and vertical evolution would permit.
A virus serves as the agent of transfer between bacterial strains.
DNA released from a bacterium is picked up by a new cell.
After the new DNA is introducedwhether via conjugation, transduction, or transformationit is incorporated into the cell and results in the emergence of a new, resistant genotype.
|Type of bacteria
||Penicillin and other b-lactam
|Proteus mirabilis (rheumatoid arthritis,
urinary tract infections)
|Klebsiella pneumoniae (ankylosing spondylitis,
a disease of the joints)
Some mechanisms of resistance
There are a number of ways enzymes have been used by bacteria to confer antibiotic
- Resist b-lactam antibiotics through modifications
in the genetic code for the proteins that bind penicillin.
- Genes for enzymes that can destroy or disable antibiotics are acquired or
arise through mutation. For example, a b-lactamase
enzyme can destroy the b-lactam ring of penicillins
through hydrolysis, and without a b-lactam ring, penicillins
are ineffective against the bacteria.
- Prevent aminoglycoside disruption of ribosomes. A bacterial enzyme adds
a bulky substituent to the aminoglycoside, making it impossible for the drug
to fit into the rRNA pocket and rendering it harmless.
The ribosome can be methylated so that an antibiotic cannot bind to it.
For antibiotics that target DNA gyrase, the enzyme that unwinds DNA for replication,
random mutations in the bacterial DNA may alter the gyrase and make it unrecognizable
to antibiotics while still leaving it functional.
In the case of sulfonamides, which operate by mimicking PABA and competing
for an enzyme that synthesizes folic acid, an increase in the amount of PABA
can outcompete the sulfonamide and render it ineffective; or an alteration in
the code for the enzyme itself can prevent its sulfonamide binding.
Effluxing the toxin
One particularly active way a bacterium may deal with an antibiotic is to pump
it out, perhaps using proteins encoded by acquired genes. For example, a strain
of enterococcal bacteria can pump out tetracycline. This type of pumping
is called an efflux phenomenon.
Note: Bacteria without inherent antibiotic resistance
can acquirethrough conjugation, transduction, or transformationthe
genes that encode proteins that confer resistance.
WHAT THE FUTURE HOLDS
We use antibiotics for everything from treating viral infectionsagainst
which antibiotics are uselessto promoting the growth of livestock to curing
acne. People often demand antibiotics from their doctors even in the absence
of proof of a bacterial infection. And people often neglect to complete a full
course of antibiotics once it has been prescribed.
The more often we use antibiotics, the more likely it is that resistance will
develop and spread. Today, about 30% of Streptococcus pneumoniae strains
are resistant to penicillin, and 30% of gonorrhea bacteria are resistant to penicillin
or tetracycline or both. Salmonella typhimurium is resistant to ampicillin,
sulfa drugs, streptomycin, tetracycline, and chloramphenicol. Even the antibiotic
of last resort, vancomycin, has become ineffectual against some superstrains.
Researchers are turning now to synthetic antibiotics for help against these superbugs.
The good news may be that resistance can disappear in the same way it developed.
Mutations that reduce resistance may occur, and if the antibiotic is not present,
there is no selective pressure to maintain resistance. In the absence of selective
pressure, the bacteria may eventually lose all of their resistance.